Liver fibrosis is a form of scar formation that is found in almost all patients with chronic injury to the liver. Over time it frequently progresses to cirrhosis, an end-stage lethal disease which is the seventh leading cause of death in the United States and afflicts hundreds of millions of people worldwide. Alcohol intake remains the most important cause of liver cirrhosis in Western countries. Alcoholic liver disease can be divided in various stages of development: (1) mild alcoholic liver injury, (2) steatosis, (3) alcoholic hepatitis, (4) alcoholic liver fibrosis and (5) cirrhosis. Although several pharmacological therapies have been tried in patients with alcoholic liver disease, none of the therapeutics so far has shown consistent improvement in the course of alcoholic liver damage and there remains a major unmet medical need for effective therapies. In our preliminary data, we show that modulators of endogenous ATRA levels have anti-fibrotic activity in mice. We have identified a novel series of ATRA modulators with excellent in vitro and in vivo pharmacological properties and demonstrate its anti-fibrotic activity in vivo. We propose to pursue the lead compound from this series towards an IND nomination as a potential therapeutic for alcoholic liver disease. PUBLIC HEALTH RELEVANCE: Liver fibrosis is a form of scar formation that is found in almost all patients with chronic injury to the liver caused by sustained immoderate alcohol consumption. Over time it frequently progresses to cirrhosis, an end- stage lethal disease which is the seventh leading cause of death in the United States and afflicts hundreds of millions of people worldwide. There is no therapeutic that shows consistent improvement in the course of alcoholic liver damage and there remains a major unmet medical need for effective therapies. In our preliminary data, we show that modulators of endogenous ATRA levels have anti-fibrotic activity in mice and that we have identified a novel, in vivo efficacious, series of ATRA modulators. We propose to pursue the lead compound from this series towards an IND nomination as a potential therapeutic for alcoholic liver disease.